Systemic lupus erythematosus (SLE) is a complex, multigenic, poorly known autoimmune disorder with susceptibility determined by a combination of genetic, environmental and stochastic factors. Recently, through linkage analysis, we have identified (Namjou et al. 2002) a potential genomic region at 5p15.3, which most likely contains a novel susceptibility gene for SLE. This finding was based on a selected group of SLE families, where at least 2 family members have a clinical presentation that is quite reminiscent of rheumatoid arthritis (SLE-RA). Now, we have replicated our initial linkage signal at 5p15 from an independent dataset consists of 88 such families SLE-RA families (Nath et al. 2004b). The suspected chromosomal region spans approximately 16 cM. Our new results not only confirm the linkage but also increase the likelihood of finding the causative SLE gene(s) at 5p15.5. The overall goal of this proposal is to narrow this susceptibility region and identify the SLE susceptibility gene contained in this region. We will achieve this by iterative reduction in the size of the chromosomal region. To improve the power of the study, Specific Aim 1 is to augment our currently available 102 SLE-RA families with approximately 23 new families expected to be identified from our ongoing SLE genetic linkage projects. We will then narrow our previously identified susceptibility region in two steps. First, in Specific Aim 2, we will choose microsatellite markers to form approximately 1 cM map across the current susceptibility region and analyze these data using genetic linkage methods. Second, in Specific Aim 3, we will choose single nucleotide polymorphism (SNP) markers to form a 0.05 cM or better map across the reduced region from specific aim 2 and analyze these data using linkage disequilibrium methods. In the next step, Specific Aim 4, we will search the public databases for SNPs in genes known to be located in the narrowed susceptibility region established by specific aim 3 and to analyze these using linkage disequilibrium methods. Finally, the Specific Aim 5 is to sequence the gene (or genes) within this linkage interval to find the causal mechanisms. For disorders with an unknown biochemical basis like SLE, identification of the genes is a very important component to their understanding of its biological basis. Therefore, identification of genes associated with the development of SLE will increase our understanding of the underlying cause of this disease. By applying both molecular genetic and genetic epidemiological techniques, this project has the potential to narrow the candidate region to a sufficiently small interval to identify this SLE susceptibility gene.